PROJECT SUMMARY The innate immune recognition of dengue virus infection triggers antiviral immune responses; however, there is little information about how the virus regulates these measures or how these responses affect dengue virus (DENV) disease pathogenesis and immunity. System biology approaches aimed at deciphering the complex interactions between DENV and host genes and pathways require accurate high-throughput measurements and comprehensive datasets and models. The purpose of this HIPC is to take advantage of recent advances in human immune profiling methods to characterize the early states of the human innate immune system following DENV infection and before and after vaccination against this infectious disease. The goal of the Genomics Core is to provide a central knowledge base and resource to define the human immune repertoire and develop predictors of disease and vaccine responses by using high throughput sequencing and bioinformatics that facilitate investigations of human immunity in well-characterized human cohorts. Other HIPC investigators will use this information to derive human immune profiles or signatures for disease in naturally acquired infection with known dengue immune status (Project 1), vaccine responsiveness and human challenge studies (Project 2), or DENV infection ex vivo with DENV strains of different virulence (Project 3). Network analysis of the human immune profiling data will identify pathways and genes for RNAi knockdown to determine how perturbations of the regulatory networks influence host responses during DENV infection. These studies are key to the overall goal of the HIPC to use high-throughput systems biology approaches to create molecular signatures that will define the human immune response profiles that correlate with the outcome of dengue virus infection or vaccination.